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DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells [csRNA-seq]

ABSTRACT: DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells [csRNA-seq]

PROVIDER: PRJNA714079 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13953406.fastq.gz	Fastqsanger.gz
	SRR13953407.fastq.gz	Fastqsanger.gz
	SRR13953408.fastq.gz	Fastqsanger.gz
	SRR13953409.fastq.gz	Fastqsanger.gz
	SRR13953410.fastq.gz	Fastqsanger.gz

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DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells [csRNA-seq]

Project description:DNMT3A encodes an enzyme that carries out de novo DNA methylation, which is essential for the acquisition of cellular identity and specialized functions during cellular differentiation. It is the most common driver gene of age-related clonal hematopoiesis. As such, mature immune cells harboring DNMT3A mutations can be readily detected in elderly individuals. Most acquired DNMT3A mutations are heterozygous and predicted to cause loss-of-function, indicating that haploinsufficiency is the predominant pathogenic mechanism. Yet, whether and how DNMT3A haploinsufficiency affects the function of mature immune cells is poorly understood. Here, we demonstrate that DNMT3A haploinsufficiency impairs the gain of DNA methylation at decommissioned enhancers, while simultaneously and unexpectedly impairs DNA demethylation at thousands of newly activated enhancers in mature human myeloid cells. The DNA methylation defects alter the activity of affected enhancers, leading to abnormal gene expression and impaired immune response. These findings provide insights into the mechanism of immune dysfunction associated with acquired DNMT3A mutations and clonal hematopoiesis.

2021-04-12 | GSE168811 | GEO

DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells [RNA-seq]

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DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells [BiSulfite-seq]

2021-04-12 | GSE168715 | GEO

DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells [tiling array]

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DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells

Project description:DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells

| PRJNA713766 | ENA

DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells [BiSulfite-seq]

Project description:DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells [BiSulfite-seq]

| PRJNA713786 | ENA

DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells [tiling array]

Project description:DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells [tiling array]

| PRJNA708327 | ENA

DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells [RNA-seq]

Project description:DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells [RNA-seq]

| PRJNA714078 | ENA

DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells.

Project description:DNMT3A encodes an enzyme that carries out de novo DNA methylation, which is essential for the acquisition of cellular identity and specialized functions during cellular differentiation. DNMT3A is the most frequently mutated gene in age-related clonal hematopoiesis. As such, mature immune cells harboring DNMT3A mutations can be readily detected in elderly persons. Most DNMT3A mutations associated with clonal hematopoiesis are heterozygous and predicted to cause loss of function, indicating that haploinsufficiency is the predominant pathogenic mechanism. Yet, the impact of DNMT3A haploinsufficiency on the function of mature immune cells is poorly understood. Here, we demonstrate that DNMT3A haploinsufficiency impairs the gain of DNA methylation at decommissioned enhancers, while simultaneously and unexpectedly impairing DNA demethylation of newly activated enhancers in mature human myeloid cells. The DNA methylation defects alter the activity of affected enhancers, leading to abnormal gene expression and impaired immune response. These findings provide insights into the mechanism of immune dysfunction associated with clonal hematopoiesis and acquired DNMT3A mutations.

| S-EPMC8111463 | biostudies-literature

DNMT3A haploinsufficiency predisposes hematopoietic cells to myeloid malignancies

Project description:DNMT3A (which encodes a de novo DNA methyltransferase) is one of the most frequently mutated genes in AML genomes. Point mutations at position R882 have been shown to cause a dominant negative loss of DNMT3A methylation activity, but 15% of DNMT3A mutations are predicted to produce truncated proteins, which could either have dominant negative activities, or cause loss-of-function and haploinsufficiency. We demonstrate that three of these mutants produce truncated, inactive proteins that do not dimerize with wild-type DNMT3A, strongly supporting the haploinsufficiency hypothesis. We therefore evaluated hematopoiesis in mice heterozygous for a constitutive null Dnmt3a mutation: unmanipulated mice developed myeloid skewing over time, and their stem/progenitor cells exhibited a long-term competitive transplantation advantage. Dnmt3a+/- mice spontaneously developed transplantable myeloid malignancies after a long latent period, and three of 12 tumors tested had cooperating mutations in the Ras- MAPK pathway. The residual Dnmt3a allele was neither mutated nor downregulated in tumors. The bone marrow cells of Dnmt3a+/- mice had a subtle but significant DNA hypomethylation phenotype that was not associated with gene dysregulation. These data demonstrate that haploinsufficiency for DNMT3A alters hematopoiesis, and predisposes mice (and probably humans) to myeloid malignancies by a mechanism that is not yet clear.

2017-08-01 | GSE100702 | GEO

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